As an initial approach, the research proposed in this application will identify specific subtypes of nicotinic acetyicholine receptor (nAChR) present in the nigrostriatal system which may be investigated for development of novel therapeutics for treatment of Parkinson's disease. Evidence that nAChRs may provide a therapeutic target for treatment include: (i) the demonstration of an inverse relationship between smoking and the incidence of PD; (ii) alleviation of the locomotor symptoms of PD with nAChR agonist administration; (iii) selective changes in expression of nAChR mRNAs in squirrel monkeys lesioned with the nigrostnatal toxin MPTP; and (iv) preliminary results indicating alterations in nAChR binding in parkinsonian non-human primates. Nicotinic receptor subtypes expressed in the nigrostriatal system will be investigated using 1251-epibatidine, 3H-cytisine, and '251-a-bungarotoxin autoradiography and competition with subtype-selective IIAChR ligands in the substantia mgra, caudate, and putamen of control and parkinsonian monkeys and the neurotransmitter makeup to which specific subunits colocalize will be determined by dual label in situ hybridization in the substantia nigra.